Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis the liver, eventually leads to insulin resistance type 2 diabetes (T2D). The goal of this study was understand mechanisms by which administration bilirubin, a powerful antioxidant, reduces hyperglycemia ameliorates obesity leptin-receptor-deficient (db/db) diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin vehicle ip. Blood glucose body weight...

SAP97 is a modular protein composed of three PDZ domains, an SH3 domain, and guanylate kinase-like domain. It has been implicated functionally in the assembly structural stability synaptic junctions as well trafficking, recruitment, localization specific ion channels neurotransmitter receptors. The N terminus (S97N) shown to play key role selection binding partners at adhesion sites, clustering heterologous cells. Using S97N domain bait yeast two-hybrid screen, we identified...

Adenoviral vectors based on serotype 5 (Ad5) have been widely used to deliver therapeutic genes different organs and tissues. However, many tissues are poorly infected with Ad5 because of low-level expression its primary receptor, coxsackievirus-adenovirus receptor (CAR). Two motifs, RGD polylysine (pK7), shown enhance infection via CAR-independent pathways when incorporated into fiber separately. Because the two motifs bind cell surface proteins (RGD motif binds integrins, pK7 heparan...

The synapse-associated protein SAP97 is a member of novel family cortical cytoskeletal proteins involved in the localization ion channels at such membrane specializations as synaptic junctions. These multidomain have binding sites for 4.1, GKAPs/SAPAPs, voltage- and ligand-gated cell-adhesion molecules containing C-terminal T/SXV motifs. In this study, we evaluated contribution individual domains to its selective recruitment attachment cytoskeleton epithelial cells. We find that PDZ, SH3 GK...

Glucagon-like peptide 1 (GLP-1) is known to suppress glucagon secretion, but the mechanism by which GLP-1 exerts this effect unclear. In study, we demonstrated receptor (GLP-1R) expression in α-cells using both antibody-dependent and antibody-independent strategies. A novel α-cell–specific GLP-1R knockout (αGLP-1R−/−) mouse model was created used investigate its effects on secretion glucose metabolism. Male female αGLP-1R−/− mice showed higher nonfasting levels than their wild-type...

Adenovirus serotype 5 (Ad5) has great potential for gene therapy applications. A major limitation, however, is the host immune response against Ad5 infection that often prevents readministration of vectors. In this regard, most abundant capsid protein, hexon, been implicated as target neutralizing antibodies. study, we sought to escape neutralization via hexon replacement. We constructed a chimeric adenovirus vector, Ad5/H3, by replacing with Ad3. The viruses were successfully rescued in 293...

Adenovirus type 5 (Ad5) is one of the most promising vectors for gene therapy applications. Genetic engineering Ad5 capsid proteins has been employed to redirect vector tropism, enhance infectivity, or circumvent preexisting host immunity. As abundant protein, hexon modification particularly attractive. However, genetic often results in failure rescuing viable viruses. Since hypervariable regions (HVRs) are nonconserved among hexons different serotypes, we investigated whether HVRs could be...

Transforming growth factor (TGF)-beta1 induces fibroblast transdifferentiation to myofibroblasts, a process that requires the involvement of integrin-mediated signaling and focal adhesion kinase (FAK). FAK-related non-kinase (FRNK) is known for its role in inhibiting cell migration; however, myofibroblast differentiation has not been defined. Here, we report FRNK abrogates TGF-beta1-induced vitro vivo. TGF-beta1 can induce alpha-smooth muscle actin (alpha-SMA) expression presence or absence...

Following intravascular delivery, an important route of administration for many clinical applications, the liver is predominant site adenovirus serotype 5 (Ad5) sequestration, thereby posing a risk toxicity. In this regard, it has recently been shown that Ad5 capsid binds to blood coagulation factor X (FX) via hexon protein. This interaction mediates majority transduction. Patient FX levels can be diminished by warfarin, vitamin K inhibitor in decreases production; however, warfarin potent...

The non-β endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing β-cells regulation of blood-glucose homeostasis. While significant progress has been made towards understanding β-cell regeneration adults, very little is known about such as glucagon-producing α-cells somatostatin producing δ-cells. Previous studies have noted increase α-cell composition diabetes patients animal models. It thus our hypothesis that non-β-cells δ-cells...

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease whose underlying molecular mechanisms are largely unknown. Herein, we show that focal adhesion kinase-related nonkinase (FRNK) plays key role in limiting the development of fibrosis. Loss FRNK function vivo leads to increased an experimental mouse model. The increase confirmed at histological, biochemical, and physiological levels. Concordantly, loss results fibroblast migration myofibroblast differentiation...

The transcription factor Pax4 plays a critical role in the determination of α- versus β-cell lineage during endocrine pancreas development. In this study, we explored whether gene transfer into α-cells could convert them functional β-cells and thus provide therapeutic benefits for insulin-deficient diabetes. We found that delivered by adenoviral vector, Ad5.Pax4, induced insulin expression reduced glucagon αTC1.9 cells. More importantly, these cells exhibited glucose-stimulated secretion,...

Abstract Background Glucagon‐like peptide 1 (GLP‐1) and glucagon share the same precursor molecule proglucagon, but each arises from a distinct posttranslational process in tissue‐specific manner. Recently, it has been shown that GLP‐1 is co‐expressed with pancreatic islet cells. This study was aimed to investigate progressive changes of versus production islets during course diabetes development. Methods Both type (non‐obese mice) 2 (db/db models were employed this study. The mice monitored...

Recent studies have demonstrated that kainate receptors are associated with members of the SAP90/PSD-95 family (synapse-associated proteins (SAPs)) in neurons and SAP90 can cluster modify electrophysiological properties GluR6/KA2 when co-expressed transfected cells. In vivo, tightly binds receptor subunits, while SAP97 is only weakly associated, suggesting this glutamate differentially associates members. Here, green fluorescent protein (GFP)-tagged chimeras deletion mutants were employed to...

An advantage of the adenoviral vector is its molecular flexibility, which allows for tropism modifications purpose cell targeting. In addition to targeting ligands, capacity incorporate heterologous peptides has allowed capsid incorporation other functionalities. We have defined minor protein IX (pIX) as a locus capable presenting incorporated ligands on virion surface. Thus, we sought exploit possibility incorporating functional proteins at pIX. our current study, expand potential utility...

Abstract Purpose: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective safe modality for the treatment of cancer. However, expression primary coxsackie-adenovirus receptor is variable in advanced cancers, therefore, use heterologous receptors could be advantageous. Experimental Design: Here, we used capsid-modified increasing transduction subsequent...

Abstract Despite the many potential advantages of Ad vectors for vaccine application, full utility current vaccines may be limited by host anti-vector immune response. Direct incorporation antigens into adenovirus capsid offers a new and exciting approach vaccination strategies; this strategy exploits inherent antigenicity vector. Critical to exploiting in context is placement antigenic epitopes within major protein, hexon. In our study we illustrate that have capability place range Ad5...

Myosin VI is an actin-based motor protein that enriched at the postsynaptic density and appears to interact with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptors (AMPARs) via synapse associated 97 (SAP97). Here, we find a Flag epitope-tagged dominant negative construct inhibits interaction between SAP97 myosin (Flag-myoVI-DN) causes dramatic reduction in number of synapses surface expression AMPARs cultured hippocampal neurons. Furthermore, Flag-myoVI-DN also...

Adenoviral (Ad) vectors have been used for a variety of vaccine applications including cancer and infectious diseases. Traditionally, Ad-based vaccines are designed to express antigens through transgene expression given antigen. However, in some cases these conventional had sub-optimal clinical results. These results attributed part pre-existing Ad serotype 5 (Ad5) immunity. In order circumvent the need antigen via incorporation, "antigen capsid-incorporation" strategy has developed...

Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and less side-effects, especially in combination with other agents. The aim of the study is investigate effect docetaxel alone combined (−)-epigallocatechin-3-gallate (EGCG) preclinical settings gastric cancer. BGC-823 human cancer xenograft model was used, tumor growth, side-effects mice were closely monitored. Expression vascular endothelial growth factor CD31 observed...

Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI(4,5)P(2)] 5-phosphatase, and mutations OCRL cause Dent disease, both which are frequently associated with hypercalciuria. Transient receptor potential, vanilloid subfamily, subtype 6 (TRPV6) an intestinal epithelial Ca(2+) channel mediating active absorption. Hyperabsorption was found in patients disease increased excretion. In this study, we tested whether TRPV6 regulated by and, if so, to...